tbuckley/cabot-search huggingface dataset:
Spatial metabolomics for evaluating response to neoadjuvant therapy in non‐small cell lung cancer patients
Authors: Jian Shen, Na Sun, Philipp Zens, Thomas Kunzke, Achim Buck, Verena M. Prade, Jun Wang, Qian Wang, Ronggui Hu, Annette Feuchtinger, Sabina Berezowska, Axel Walch
Journal: Cancer Communications (2022)

The response to neoadjuvant chemotherapy (NAC) differs substantially among individual patients with non-small cell lung cancer (NSCLC). Major pathological response (MPR) is a histomorphological read-out used to assess treatment response and prognosis in patients NSCLC after NAC. Although spatial metabolomics is a promising tool for evaluating metabolic phenotypes, it has not yet been utilized to assess therapy responses in patients with NSCLC. We evaluated the potential application of spatial metabolomics in cancer tissues to assess the response to NAC, using a metabolic classifier that utilizes mass spectrometry imaging combined with machine learning.
Tacrolimus-binding protein FKBP8 directs myosin light chain kinase-dependent barrier regulation and is a potential therapeutic target in Crohn’s disease
Authors: Li Zuo, Wei-Ting Kuo, Feng Cao, Sandra D Chanez-Paredes, Daniel Zeve, Prabhath Mannam, Léa Jean-François, Anne Day, W Vallen Graham, Yan Y Sweat, Nitesh Shashikanth, David T Breault, Jerrold R Turner
Journal: Gut (2022)

Objective Intestinal barrier loss is a Crohn’s disease (CD) risk factor. This may be related to increased expression and enzymatic activation of myosin light chain kinase 1 (MLCK1), which increases intestinal paracellular permeability and correlates with CD severity. Moreover, preclinical studies have shown that MLCK1 recruitment to cell junctions is required for tumour necrosis factor (TNF)-induced barrier loss as well as experimental inflammatory bowel disease progression. We sought to define mechanisms of MLCK1 recruitment and to target this process pharmacologically. Design Protein interactions between FK506 binding protein 8 (FKBP8) and MLCK1 were assessed in vitro. Transgenic and knockout intestinal epithelial cell lines, human intestinal organoids, and mice were used as preclinical models. Discoveries were validated in biopsies from patients with CD and control subjects. Results MLCK1 interacted specifically with the tacrolimus-binding FKBP8 PPI domain. Knockout or dominant negative FKBP8 expression prevented TNF-induced MLCK1 recruitment and barrier loss in vitro. MLCK1-FKBP8 binding was blocked by tacrolimus, which reversed TNF-induced MLCK1-FKBP8 interactions, MLCK1 recruitment and barrier loss in vitro and in vivo. Biopsies of patient with CD demonstrated increased numbers of MLCK1-FKBP8 interactions at intercellular junctions relative to control subjects. Conclusion Binding to FKBP8, which can be blocked by tacrolimus, is required for MLCK1 recruitment to intercellular junctions and downstream events leading to immune-mediated barrier loss. The observed increases in MLCK1 activity, MLCK1 localisation at cell junctions and perijunctional MLCK1-FKBP8 interactions in CD suggest that targeting this process may be therapeutic in human disease. These new insights into mechanisms of disease-associated barrier loss provide a critical foundation for therapeutic exploitation of FKBP8-MLCK1 interactions.
Abstract B004: Adaptive therapy in preclinical models of hormone-refractory breast cancer
Authors: Sareh Seyedi, Carlo Maley
Journal: Cancer Research (2022)

Abstract The goal of this study was to test whether adaptive therapy works in preclinical mouse models with hormone-refractory breast cancer and compare adaptive therapy with standard therapy. Specifically, we tested whether the drugs gemcitabine and/or capecitabine can control the MCF7 cancer cell line which is resistant to palbociclib and fulvestrant. We treated MCF7 resistant breast cancers growing orthotopically in the mammary fat pads of NSG immunodeficient mice with gemcitabine, capecitabine, or both drugs together. In the combined drug treatment, we switched drugs in every application (every 3 days) (“ping-pong”) or applied the drugs together (in tandem). In both single and multi-drug therapy, we applied drugs by either adjusting their doses or applying intermittently. We measured tumor size by bioluminescence imaging and caliper. We saw a reduction in the tumor burden of most mice treated with adaptive therapy along with prolonging overall survival. We found that the combination of gemcitabine and capecitabine in both intermittent and dose adjustment protocols significantly increased the survival of mice in comparison to standard therapy when we applied the drugs in a ping-pong strategy. The combination therapy in tandem was less successful compared to dose adjustment, but better than standard therapy in increasing overall survival. Moreover, we had several weeks off-treatment in most of the mice when the tumor was under the threshold, therefore lower drug doses were used. Among single drug therapies, capecitabine dose adjustment protocol was better than using both intermittent and the maximum tolerated dose in terms of increasing overall survival of mice and accumulating less dose of the drug. However, the capecitabine intermittent treatment was better compared to the capecitabine maximum tolerated dose. In contrast, there were no significant differences between adaptive protocols and standard therapy. However, in both intermittent and dose adjustment protocols we had several weeks off-treatment in most of the mice, so lower drug doses were used. In conclusion, we found that lower drug doses can be used under adaptive therapy, once the tumor is controlled. We had several weeks off- treatment for some cases and we saw a continued decline in tumor size. Overall, adaptive therapy strategies could prolong progression-free survival besides reduction in the tumor burden. Citation Format: Sareh Seyedi, Carlo Maley. Adaptive therapy in preclinical models of hormone-refractory breast cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr B004.
Unusual application of an endoscopic–laparoscopic rendezvous technique to restore the percutaneous gastrostomy in buried bumper syndrome
Authors: Roberto Di Mitri, Michele Amata, Ambra Bonaccorso, Filippo Mocciaro, Elisabetta Conte, Barbara Scrivo, Daniela Scimeca
Journal: Endoscopy (2022)

A 66-year-old man with cerebrovascular disease underwent placement of a percutaneous endoscopic gastrostomy (PEG) using a 20-Fr dome-bolstered tube. After 1-month, the patient was admitted to our institute for investigation of infusion resistance and leakage around the tube. On physical examination, the internal bumper was not rotatable or moveable, and was subcutaneously palpable. A computed tomography scan confirmed dislocation of the peritoneal bumper ([Fig. 1 a]). Endoscopically, just a small dimple was visible in the mucosa of the anterior wall of the stomach ([Fig. 1 b]), confirming the diagnosis of complete buried bumper syndrome. The PEG was removed with gentle external traction.
Reply to the commentaries: A radical revision of experimental social psychology is still needed
Authors: Joseph Cesario
Journal: Behavioral and Brain Sciences (2022)

Abstract Are the landscapes of real-world decisions adequately represented in our laboratory tasks? Are the goals and expertise of experimental participants the same as real-world decision-makers? Are we neglecting crucial forces that lead to group outcomes? Are the contingencies necessary for producing experimental demonstrations of bias present in the real world? In the target article, I argued that the answers to these questions are needed to understand whether and how laboratory research can inform real-world group disparities. Most of the commentaries defending experimental social psychology neglected to directly address these main arguments. The commentaries defending implicit bias only revealed the inadequacy of this concept for explaining group disparities. The major conclusions from the target article remain intact, suggesting that experimental social psychology must undergo major changes to contribute to our understanding of group disparities.
Re: Yaw A. Nyame, Matthew R. Cooperberg, Marcus G. Cumberbatch, et al. Deconstructing, Addressing, and Eliminating Racial and Ethnic Inequities in Prostate Cancer Care. Eur Urol. In press. https://doi.org/10.1016/j.eururo.2022.03.007
Authors: Yu Wei, Dingwei Ye, Yao Zhu
Journal: European Urology (2022)
Long-term efficacy, safety and neurotolerability of MATRix regimen followed by autologous transplant in primary CNS lymphoma: 7-year results of the IELSG32 randomized trial
Authors: Andrés J M Ferreri, Kate Cwynarski, Elisa Pulczynski, Christopher P Fox, Elisabeth Schorb, Claudia Celico, Monica Falautano, Alessandro Nonis, Paul La Rosée, Mascia Binder, Alberto Fabbri, Fiorella Ilariucci, Mauro Krampera, Alexander Roth, Claire Hemmaway, Peter W Johnson, Kim M Linton, Tobias Pukrop, Jettes Sønderskov Gørløv, Monica Balzarotti, Georg Hess, Ulrich Keller, Stephan Stilgenbauer, Jense Panse, Alessandra Tucci, Lorella Orsucci, Francesco Pisani, Manuela Zanni, Stefan W Krause, Hans J Schmoll, Bernd Hertenstein, Mathias Rummel, Jeffery Smith, Lorenz Thurner, Giuseppina Cabras, Elsa Pennese, Maurilio Ponzoni, Martina Deckert, Letterio S Politi, Jurgen Finke, Antonella Ferranti, Kelly Cozens, Elvira Burger, Nicoletta Ielmini, Franco Cavalli, Emanuele Zucca, Gerald Illerhaus
Journal: Leukemia (2022)
Development of human pluripotent stem cell-derived hepatic organoids as an alternative model for drug safety assessment
Authors: Hyemin Kim, Ilkyun Im, Jang Su Jeon, Eun-Hye Kang, Hyang-Ae Lee, Seongyea Jo, Ji-Woo Kim, Dong-Hun Woo, Young Jae Choi, Hyo Jin Kim, Ji-Seok Han, Byoung-Seok Lee, Jong-Hoon Kim, Sang Kyum Kim, Han-Jin Park
Journal: Biomaterials (2022)

Human in vitro hepatic models that faithfully recapitulate liver function are essential for successful basic and translational research. A limitation of current in vitro models, which are extensively used for drug discovery and toxicity testing, is the loss of drug metabolic function due to the low expression and activity of cytochrome P450 (CYP450) enzymes. Here, we aimed to generate human pluripotent stem cell-derived hepatic organoids (hHOs) with a high drug metabolic ability. We established a two-step protocol to produce hHOs from human pluripotent stem cells for long-term expansion and drug testing. Fully differentiated hHOs had multicellular composition and exhibited cellular polarity and hepatobiliary structures. They also displayed remarkable CYP450 activity and recapitulated the metabolic clearance, CYP450-mediated drug toxicity, and metabolism. Furthermore, hHOs successfully modeled Wilson's disease in terms of Cu metabolism, drug responses, and diagnostic marker expression and secretion. In conclusion, hHOs exhibit high capacity for drug testing and disease modeling. Hence, this hepatic model system provides an advanced tool for studying hepatic drug metabolism and diseases.
Giant <i>Starship</i> Elements Mobilize Accessory Genes in Fungal Genomes
Authors: Emile Gluck-Thaler, Timothy Ralston, Zachary Konkel, Cristhian Grabowski Ocampos, Veena Devi Ganeshan, Anne E. Dorrance, Terry L. Niblack, Corlett W. Wood, Jason C. Slot, Horacio D. Lopez-Nicora, Aaron A. Vogan
Journal: Molecular Biology and Evolution (2022)

Accessory genes are variably present among members of a species and are a reservoir of adaptive functions. In bacteria, differences in gene distributions among individuals largely result from mobile elements that acquire and disperse accessory genes as cargo. In contrast, the impact of cargo-carrying elements on eukaryotic evolution remains largely unknown. Here, we show that variation in genome content within multiple fungal species is facilitated by Starships, a newly discovered group of massive mobile elements that are 110 kb long on average, share conserved components, and carry diverse arrays of accessory genes. We identified hundreds of Starship-like regions across every major class of filamentous Ascomycetes, including 28 distinct Starships that range from 27 to 393 kb and last shared a common ancestor ca. 400 Ma. Using new long-read assemblies of the plant pathogen Macrophomina phaseolina, we characterize four additional Starships whose activities contribute to standing variation in genome structure and content. One of these elements, Voyager, inserts into 5S rDNA and contains a candidate virulence factor whose increasing copy number has contrasting associations with pathogenic and saprophytic growth, suggesting Voyager's activity underlies an ecological trade-off. We propose that Starships are eukaryotic analogs of bacterial integrative and conjugative elements based on parallels between their conserved components and may therefore represent the first dedicated agents of active gene transfer in eukaryotes. Our results suggest that Starships have shaped the content and structure of fungal genomes for millions of years and reveal a new concerted route for evolution throughout an entire eukaryotic phylum.
Precision medicine: In vivo CAR therapy as a showcase for receptor-targeted vector platforms
Authors: Alexander Michels, Naphang Ho, Christian J. Buchholz
Journal: Molecular Therapy (2022)

Chimeric antigen receptor (CAR) T cells are a cancer immunotherapy of extremes. Unprecedentedly effective, but complex and costly to manufacture, they are not yet a therapeutic option for all who would benefit. This disparity has motivated worldwide efforts to simplify treatment. Among the proposed solutions, the generation of CAR T cells directly in the patient, i.e., in vivo, is arguably simultaneously the most technically challenging and clinically useful approach to convert CAR therapy from a cell-based autologous medicinal product into a universally applicable off-the-shelf treatment. Here, we review the current state of the art of in vivo CAR therapy, focusing especially on the vector technologies used. These cover lentiviral vectors and adenovirus-associated vectors as well as synthetic polymer nanocarriers and lipid nanoparticles. Proof of concept, i.e., the generation of CAR cells directly in mouse models, has been demonstrated for all vector platforms. Receptor targeting of vector particles is crucial, as it can prevent CAR gene delivery into off-target cells, thus reducing toxicities. We discuss the properties of the vector platforms, such as their immunogenicity, potency, and modes of CAR delivery (permanent versus transient). Finally, we outline the work required to advance in vivo CAR therapy from proof of concept to a robust, scalable technology for clinical testing. Chimeric antigen receptor (CAR) T cells are a cancer immunotherapy of extremes. Unprecedentedly effective, but complex and costly to manufacture, they are not yet a therapeutic option for all who would benefit. This disparity has motivated worldwide efforts to simplify treatment. Among the proposed solutions, the generation of CAR T cells directly in the patient, i.e., in vivo, is arguably simultaneously the most technically challenging and clinically useful approach to convert CAR therapy from a cell-based autologous medicinal product into a universally applicable off-the-shelf treatment. Here, we review the current state of the art of in vivo CAR therapy, focusing especially on the vector technologies used. These cover lentiviral vectors and adenovirus-associated vectors as well as synthetic polymer nanocarriers and lipid nanoparticles. Proof of concept, i.e., the generation of CAR cells directly in mouse models, has been demonstrated for all vector platforms. Receptor targeting of vector particles is crucial, as it can prevent CAR gene delivery into off-target cells, thus reducing toxicities. We discuss the properties of the vector platforms, such as their immunogenicity, potency, and modes of CAR delivery (permanent versus transient). Finally, we outline the work required to advance in vivo CAR therapy from proof of concept to a robust, scalable technology for clinical testing.
A Composite End Point of Graft Status and eGFR at 1 Year to Improve the Scientific Registry of Transplant Recipients’ Five-Tier Rating System
Authors: Kaicheng Wang, Yanhong Deng, Darren Stewart, Richard N. Formica
Journal: Journal of the American Society of Nephrology (2022)

Performance of kidney transplant programs in the United States is monitored and publicly reported by the Scientific Registry of Transplant Recipients (SRTR). With relatively few allograft failure events per program and increasing homogeneity in program performance, quantifying meaningful differences in program competency based only on 1-year survival rates is challenging.We explored whether the traditional end point of allograft failure at 1 year can be improved by incorporating a measure of allograft function (i.e., eGFR) into a composite end point. We divided SRTR data from 2008 through 2018 into a training and validation set and recreated SRTR tiers, using the traditional and composite end points. The conditional 5-year deceased donor allograft survival and 5-year eGFR were then assessed using each approach.Compared with the traditional end point, the composite end point of graft failure or eGFR <30 ml/min per 1.73 m2 at 1-year post-transplant performed better in stratifying transplant programs based on long-term deceased donor graft survival. For tiers 1 through 5 respectively, the 5-year conditional graft survival was 72.9%, 74.8%, 75.4%, 77.0%, and 79.7% using the traditional end point and 71.1%, 74.4%, 76.9%, 77.0%, and 78.4% with the composite end point. Additionally, with the five-tier system derived from the composite end point, programs in tier 3, tier 4, and tier 5 had significantly higher mean eGFRs at 5 years compared with programs in tier 1. There were no significant eGFR differences among tiers derived from the traditional end point alone.This proof-of-concept study suggests that a composite end point incorporating allograft function may improve the post-transplant component of the five-tier system by better differentiating between transplant programs with respect to long-term graft outcomes.
VERONICA: Randomized Phase II Study of Fulvestrant and Venetoclax in ER-Positive Metastatic Breast Cancer Post-CDK4/6 Inhibitors – Efficacy, Safety, and Biomarker Results
Authors: Geoffrey J. Lindeman, Tharu M. Fernando, Rebecca Bowen, Katarzyna J. Jerzak, Xinni Song, Thomas Decker, Frances Boyle, Steve McCune, Anne Armstrong, Catherine Shannon, Gianfilippo Bertelli, Ching-Wei Chang, Rupal Desai, Kushagra Gupta, Timothy R. Wilson, Aulde Flechais, Aditya Bardia
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Despite promising activity in hematopoietic malignancies, efficacy of the B-cell lymphoma 2 (BCL2) inhibitor venetoclax in solid tumors is unknown. We report the prespecified VERONICA primary results, a randomized phase II clinical trial evaluating venetoclax and fulvestrant in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer, post–cyclin-dependent kinase (CDK) 4/6 inhibitor progression. Patients and Methods: Pre-/postmenopausal females ≥18 years were randomized 1:1 to venetoclax (800 mg orally daily) plus fulvestrant (500 mg intramuscular; cycle 1: days 1 and 15; subsequent 28-day cycles: day 1) or fulvestrant alone. The primary endpoint was clinical benefit rate (CBR); secondary endpoints were progression-free survival (PFS), overall survival, and safety. Exploratory biomarker analyses included BCL2 and BCL extra-large (BCLXL) tumor expression, and PIK3CA circulating tumor DNA mutational status. Results: At primary analysis (cutoff: August 5, 2020; n = 103), venetoclax did not significantly improve CBR [venetoclax plus fulvestrant: 11.8% (n = 6/51; 95% confidence interval (CI), 4.44–23.87); fulvestrant: 13.7% (7/51; 5.70–26.26); risk difference –1.96% (95% CI, –16.86 to 12.94)]. Median PFS was 2.69 months (95% CI, 1.94–3.71) with venetoclax plus fulvestrant versus 1.94 months (1.84–3.55) with fulvestrant (stratified HR, 0.94; 95% CI, 0.61–1.45; P = 0.7853). Overall survival data were not mature. A nonsignificant improvement of CBR and PFS was observed in patients whose tumors had strong BCL2 expression (IHC 3+), a BCL2/BCLXL Histoscore ratio ≥1, or PIK3CA-wild-type status. Conclusions: Our findings do not indicate clinical utility for venetoclax plus fulvestrant in endocrine therapy–resistant, CDK4/6 inhibitor–refractory metastatic breast tumors, but suggest possible increased dependence on BCLXL in this setting.
Macrophage-mediated tumor-targeted delivery of engineered Salmonella typhimurium VNP20009 in anti-PD1 therapy against melanoma
Authors: Leyang Wu, Lin Li, Shufeng Li, Lina Liu, Wenjie Xin, Chenyang Li, Xingpeng Yin, Xuebo Xu, Feifei Bao, Zichun Hua
Journal: Acta Pharmaceutica Sinica B (2022)

Bacterial antitumor therapy has great application potential given its unique characteristics, including genetic manipulation, tumor targeting specificity and immune system modulation. However, the nonnegligible side effects and limited efficacy of clinical treatment limit their biomedical applications. Engineered bacteria for therapeutic applications ideally need to avoid their accumulation in normal organs and possess potent antitumor activity. Here, we show that macrophage-mediated tumor-targeted delivery of Salmonella typhimurium VNP20009 can effectively reduce the toxicity caused by administrating VNP20009 alone in a melanoma mouse model. This benefits from tumor-induced chemotaxis for macrophages combined with their slow release of loaded strains. Inspired by changes in the tumor microenvironment, including a decrease in intratumoral dysfunctional CD8+ T cells and an increase in PDL1 on the tumor cell surface, macrophages were loaded with the engineered strain VNP-PD1nb, which can express and secrete anti-PD1 nanoantibodies after they are released from macrophages. This novel triple-combined immunotherapy significantly inhibited melanoma tumors by reactivating the tumor microenvironment by increasing immune cell infiltration, inhibiting tumor cell proliferation, remodeling TAMs to an M1-like phenotype and prominently activating CD8+ T cells. These data suggest that novel combination immunotherapy is expected to be a breakthrough relative to single immunotherapy.
Killing three birds with one stone: Near-infrared light triggered nitric oxide release for enhanced photodynamic and anti-inflammatory therapy in refractory keratitis
Authors: Hengrui Zhang, Wenya Jiang, Yaou Peng, Jie Yang, Xiaoying Chu, Ziyue Long, Renlong Li, Qiuwei Liang, Hao Suo, Shuting Wang, Mei Yang, Ji Qi, Dan Ding, Ying-Wei Yang, Bailiang Wang
Journal: Biomaterials (2022)